NLRP3 inflammasome in neurodegenerative disease

Published:August 08, 2022DOI:


      Neurodegenerative diseases are characterized by a dysregulated neuro-glial microenvironment, culminating in functional deficits resulting from neuronal cell death. Inflammation is a hallmark of the neurodegenerative microenvironment and despite a critical role in tissue homeostasis, increasing evidence suggests that chronic inflammatory insult can contribute to progressive neuronal loss. Inflammation has been studied in the context of neurodegenerative disorders for decades but few anti-inflammatory treatments have advanced to clinical use. This is likely due to the related challenges of predicting and mitigating off-target effects impacting the normal immune response while detecting inflammatory signatures that are specific to the progression of neurological disorders. Inflammasomes are pro-inflammatory cytosolic pattern recognition receptors functioning in the innate immune system. Compelling pre-clinical data has prompted an intense interest in the role of the NLR family pyrin domain containing 3 (NLRP3) inflammasome in neurodegenerative disease. NLRP3 is typically inactive but can respond to sterile triggers commonly associated with neurodegenerative disorders including protein misfolding and aggregation, mitochondrial and oxidative stress, and exposure to disease-associated environmental toxicants. Clear evidence of enhanced NLRP3 inflammasome activity in common neurodegenerative diseases has coincided with rapid advancement of novel small molecule therapeutics making the NLRP3 inflammasome an attractive target for near-term interventional studies. In this review, we highlight evidence from model systems and patients indicating inflammasome activity in neurodegenerative disease associated with the NLRP3 inflammasome's ability to recognize pathologic forms of amyloid-β, tau, and α-synuclein. We discuss inflammasome-driven pyroptotic processes highlighting the potential utility of evaluating extracellular inflammasome-related proteins in the context of biomarker discovery. We complete the report by pointing out gaps in our understanding of intracellular modifiers of inflammasome activity and mechanisms regulating the resolution of inflammasome activation. The literature review and perspectives provide a conceptual platform for continued analysis of inflammation in neurodegenerative diseases through the study of inflammasomes and pyroptosis, mechanisms of inflammation and cell death now recognized to function in multiple highly prevalent neurological disorders.


      ALRs (absent in melanoma 2-like receptors), α-syn (alpha-synuclein), AD (Alzheimer's disease), (amyloid beta), APP (amyloid precursor protein), ALS (amyotrophic lateral sclerosis), ASC (apoptosis-associated speck-like protein containing a CARD)), BBB (blood brain barrier), BMDMs (bone-marrow derived macrophages), CARD (caspase activation and recruitment domain), CNS (Central nervous system), CSF (cerebrospinal fluid), COPD (chronic obstructive pulmonary disease), CRID (cytokine release inhibitory drug), DAMPs (danger associated molecular patterns), DPI (diphenyliodonium), DA (dopaminergic), Drd2 (dopamine D2 receptor), ESCRT (endosomal sorting complexes required for transport), EAE (experimental autoimmune encephalomyelitis), EVs (extracellular vesicles), GSDMD (Gasdermin D), hIPSCs (human induced pluripotent stem cells), HIV-1 (human immunodeficiency virus), HLA (human leukocyte antigen), IKK (IκB kinase), IFN-β (interferon-β), LPS (lipopolysaccharide), MCI (mild cognitive impairment), MS (Multiple Sclerosis), MVBs (multivesicular bodies), NLRP3 (NLR family pyrin domain containing 3), NLRs (nucleotide-binding domain-like receptors), PD (Parkinson's disease), PAMPs (pathogen associated molecular patterns), PET (positron emission tomography), PK (pharmacokinetics), PTMs (post-translational modifications), PSEN1/PS1 (presenilin 1), PSEN2/PS2 (presenilin 2), ROS (Reactive oxygen species), RvD2 (Resolvin D2), SOD1 (superoxide dismutase 1), SNpC (substantia nigra pars compacta), TDP-43 (TAR DNA binding protein 43), TBI (traumatic brain injury), TLR (toll-like receptor), TCA (tricarboxylic acid)
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